Forty two-year-old man presented with diaphoresis, unintentional 20-lb weight loss and progressive cervical, axillary, and inguinal lymphadenopathy (LAD) in September 2014. A CT of the neck, thorax, abdomen, and pelvis (NTAP) revealed diffused bilateral cervical, left axillary, retroperitoneal, pelvic, and bilateral inguinal lymphadenopathy (largest LAD: 2.7 cm on left axilla). A left inguinal lymph node excisional biopsy showed replacement of normal lymph node architecture by two distinct Epstein-Barr virus (EBV) positive lymphomas: Burkitt lymphoma (CD20+, CD10+, BCL-2-, MUM-1+) with Ki-67% of 100% and positive t(8;14)(q24;32) in 29% of the cells, and Reed Stemberg cells positive for CD30 and in-situ hybridization for EBV (EBER), consistent with cHL. Bone marrow aspirate and biopsy (BMBx) was infiltrated by cHL (CD15+, CD30+, EBER+, PAX5+, CD20 -). He was diagnosed with HIV on December 2013 and was on antiretroviral therapy (ART) since February 2014. At diagnosis of his lymphomas, his HIV-1 viral load was undetectable and his CD4 count was 155/uL. From October 2014 to February 2015 he received six cycles of dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with intrathecal methotrexate and cytarabine prophylaxis every cycle. After completion of EPOCH-R, a CT of NTAP showed interval development of multiple liver and splenic lesions, retroperitoneal and left axillary LAD enlargement, and resolution of cervical nodes. Liver function tests (LFTs) were normal. Core needle biopsy of a liver nodule depicted cHL with no evidence of Burkitt lymphoma. BMBx had residual cHL cells (<3%) and no Burkitt lymphoma. He received three cycles of salvage chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) from February 2015 to April 2015. He was hospitalized on April 2015 with persistent fevers and malaise. CT scans confirmed progression of liver lesions with normal alanine transaminase (ALT) (3.0 mg/dl, normal range (NR): normal range: 5.0–55 U/L) and total bilirubin (TB) (0.6 mg/dl, NR: 0.2–1.2), with mild elevation of both alkaline phosphatase (AP) (181 mg/dl, NR: 40–150 U/L) and aspartate aminotransferase (AST) (39 mg/dl, NR: 5.0–34 U/L). Due to evidence of progressive disease (PD) he was switch to single agent Brentuximab-vedotin and received four doses from April 2015 to June 2015 with several delays due to cytopenias, before being readmitted with new evidence of PD on CT NCAP and on BMBx (cHL involving 70–80% on bone marrow without evidence of Burkitt lymphoma). His LFTs began to deteriorate (AST 93 IU, ALT 81 IU/L, AP 436 IU/L, and TB 1.1. mg/dl). Fourth line salvage chemotherapy with gemcitabine and cisplatin (four cycles) was given from August 2015 to October 2015 with initial resolution of constitutional symptoms and LFTs improvement, but complicated by prolonged thrombocytopenia needing frequent platelet transfusions. Restaging images in November 2015 showed PD with multiple new splenic lesions and retroperitoneal lymph node enlargement. BMBx showed persistent cHL (20% of bone marrow) with no other malignancy. In December 2015, at the time of this progression, he developed persistent fevers, abdominal distension, jaundice and worsening of his LFTs (AST 140 IU/L, ALT 68 IU/L, AP 719 IU/L and TB 4.4 mg/dl). magnetic resonance imaging (MRI) of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal LAD. The patient developed severe hepatic encephalopathy in concordance with worsening liver function (AST 129 IU/L, ALT 61 IU/L, AP 127 IU/L, albumin 2.2 mg/dl, PTT 54.4 s, PT 33.2 s, INR 2.2 and TB 14.6 mg/dl). The patient’s HIV viral load at that time was undectable with less than 40 copies/ml detected. At this moment the options were either comfort care in hospice or treatment with nivolumab. In accordance with the patient’s wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, ART was on hold due to LFTs, and CD4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal (AST 26 IU/L, ALT 15 IU/L, AP 157 IU/L and TB 1.3 mg/dl) (Fig. 1). He was able to restart his ART (CD4 count on 2/2016: 157/uL). Following 3 months of nivolumab treatment, a BMBx on March 2016 showed variable marrow cellularity with low level involvement of cHL (5%). After 5 months of nivolumab treatment (10 doses), restaging CT scan of NCAP done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non-enlarged retroperitoneal lymph nodes without intraabdominal LAD; consistent with partial response (PR). At the time of his last follow up on December 2016 (29 months after initial diagnosis and 12 months after first nivolumab dose) he continues to be asymptomatic without constitutional symptoms eastern cooperative oncology group (ECOG) performance status of 1, with normal LFTs (AST 26 IU/L, ALT 15 IU/L, AP 157 IU/L and TB 1.3 mg/dl) and only mild thrombocytopenia (126.000/mm3) (Fig. 2). Importantly, both HIV-1 viral load and CD4 counts have remain stable on ART (undetectable and 126/uL, respectively), and he has not experience any immune related adverse events (irAEs) after 24 doses of nivolumab on his continued therapy with ART regimen (elvitegravir, cobicistat, emtricitabine and tenofovir.)